Solid Pharmaceutical Preparations Containing Copolymers Based On Polyethers Combined With Poorly Water-Soluble Polymers

ABSTRACT

The invention relates to dosage forms which contain preparations of poorly water-soluble substances in a polymer matrix of polyether copolymers, said polyether copolymers being obtained by the radically initiated polymerization of a mixture from 30 to 80% by weight of N-vinyl lactam, 10 to 50% by weight of vinyl acetate and 10 to 50% by weight of a polyether, and at least one poorly water-soluble polymer, the poorly water-soluble substance being present in the polymer matrix as an amorphous substance.

The present invention relates to solid pharmaceutical preparations ofpolyether copolymers, which are obtained by polymerization of vinylacetate and N-vinyllactams in the presence of a polyether, and slightlywater-soluble active substances, in combination with further polymerswhich are capable of influencing the stability of the formulation and/orthe release of the biologically active substance. Furthermore, theinvention relates to processes for the production of these preparationsand the use thereof.

The corresponding polyether copolymers act as solubilizers for theslightly water-soluble biologically active substances.

In the production of homogeneous preparations, in particular ofbiologically active substances, the solubilization of hydrophobic, i.e.slightly water-soluble, substances has become very important inpractice.

Solubilization is to be understood as meaning the imparting ofsolubility to substances which are slightly soluble or insoluble in acertain solvent, in particular water, by surface-active compounds, thesolubilizers. Such solubilizers are capable of converting poorlywater-soluble or water-insoluble substances into transparent, at mostopalescent aqueous solutions without the chemical structure of thesesubstances undergoing a change thereby (cf. Römpp Chemie Lexikon, 9thedition, vol. 5. page 4203, Thieme Verlag, Stuttgart, 1992).

In the solubilizates prepared, the poorly water-soluble orwater-insoluble substance is present as a colloidal solution in themolecular associates of the surface-active compounds which form inaqueous solution, such as, for example, hydrophobic domains or micelles.The resulting solutions are stable or metastable single-phase systemswhich appear optically transparent to opalescent.

In the case of pharmaceutical preparations, the bioavailability andhence the action of drugs can be increased by the use of solubilizers.

A further desirable requirement regarding solubilizers is the ability toform so-called “solid solutions” with slightly soluble substances. Theterm “solid solution” designates a state in which a substance isdispersed in colloidal form or ideally dispersed in molecular form in asolid matrix, for example a polymer matrix. Such solid solutions, forexample when used in solid pharmaceutical administration forms of aslightly soluble active substance, lead to improved release of theactive substance. An important requirement regarding said solidsolutions is that they are stable even on storage over a relatively longtime, i.e. that the active substance does not crystallize. Furthermore,the capacity of the solid solution, in other words the ability to formstable solid solutions having active substance contents which are ashigh as possible, is also important.

In the formation of solid solutions, the hygroscopicity of thesolubilizers also plays an important role in addition to the basicability of the solubilizers to form solid solutions. Solubilizers whichtake up too much water from the surrounding air lead to deliquescence ofthe solid solution and the undesired crystallization of the activesubstances. Excessively high hygroscopicity can also lead to problemsduring the processing to give administration forms.

Many known polymeric solubilizers have the disadvantages that they donot form stable solid solutions, in particular when the active substanceis present above the saturated concentration in the polymer. As aresult, the system is kinetically controlled and the active substance iscrystallized in the course of storage. This presents a major problem.

In addition, the known solubilizers and formulations still leave roomfor improvements, which relates to the solubilization in aqueoussystems, in particular biological systems. The oral bioavailability isfrequently not increased to the extent which would be desirable in orderto achieve a uniform, reproducible action without side effects.Regarding the processability, too, some of the known solubilizers havedisadvantages owing to their tendency to become tacky, since they arenot sufficiently flowable powders.

A further problem in the case of pharmaceutical preparations of slightlywater-soluble active substances is the control of the release.Frequently, it is not the excipient that controls the release in thecase of such forms but the crystal properties of the active substance.This means that variations in the particle size of the active substance,differences in the crystal modification and differences in the particleshape have a considerable influence on the dissolution. Since theseparameters are difficult to establish exactly, different release ratesresult. In the case of water-soluble active substances, this problem isnot present since the dissolution process of the active substance isconsiderably faster than the diffusion process which is controlled by aretardant polymer.

With regard to the release, a distinction should be made between instantrelease (fast-releasing) forms, enteric release (gastric resistant)forms and sustained release (delayed, slowly releasing) forms. Formswhich release at least 75% after 1 h are designated as instant releaseforms. In the case of enteric release forms, slight release takes placein gastric juice (<10% as a rule) but fast release in intestinal fluid.

Sustained release forms have a slow release both in gastric juice and inintestinal fluid. The term sustained release form is used when therelease is slower than 75% after 3 h.

The slightly water-soluble polymers are to be understood as meaningpolymers which are slightly soluble over the entire pH range or at leastin a certain pH range. These include so-called sustained releasepolymers (insoluble as a rule from pH 1 to 14), acidic, gastricresistant polymers (slightly soluble in the acidic pH range), and basic,reverse enteric polymers (slightly soluble in the neutral to basic pHrange). See further below for a definition of solubility.

EP-A 876 819 describes the use of copolymers of at least 60% by weightof N-vinylpyrrolidone and amides or esters having long-chain alkylgroups.

EP-A 948 957 describes the use of copolymers of monoethylenicallyunsaturated carboxylic acids, such as, for example, acrylic acid, andhydrophobically modified comonomers, such as, for example, N-alkyl- orN,N-dialkylamides of unsaturated carboxylic acids having C₈-C₃₀-alkylradicals.

DE-A 199 350 63 discloses polyalkylene oxide-containing graft polymersbased on vinyllactams and vinyl acetate and the use thereof as gashydrate inhibitors.

EP-A 953 347 discloses the use of polyalkylene oxide-containing graftpolymers as solubilizers. The graft polymers which are described thereand comprise vinyl acetate and polyalkylene oxides are frequently notpowders but viscous tacky liquids, which is a disadvantage in use.

WO 2007/051743 discloses the use of water-soluble or water-dispersiblecopolymers of N-vinyllactam, vinyl acetate and polyethers assolubilizers for pharmaceutical, cosmetic, food, agrotechnical and othertechnical applications. It is stated therein very generally that thecorresponding graft polymers can also be processed in the melt with theactive substances.

WO 2009/013202 discloses that such graft polymers of N-vinyllactam,vinyl acetate and polyethers can be melted in an extruder and mixed withpulverulent or liquid active substances, the extrusion at temperaturessubstantially below the melting point of the active substance beingdescribed.

However, a satisfactorily high and simultaneously stable activesubstance loading cannot be achieved by mixing the molten graft polymerswith pulverulent or liquid active substances. In particular, theachievement of a stable X-ray amorphous state of the active substance isnot always possible to satisfactory degrees.

It was an object of the present invention to provide improvedpreparations of slightly water-soluble active substances, whichpreparations permit targeted adjustment of the release in combinationwith good bioavailability.

Accordingly, pharmaceutical dosage forms comprising preparations ofslightly water-soluble active substances in a polymer matrix ofpolyether copolymers, the polyether copolymers being obtained by freeradical polymerization of a mixture of from 30 to 80% by weight ofN-vinyllactam, from 10 to 50% by weight of vinyl acetate and from 10 to50% by weight of a polyether, and of at least one slightly water-solublepolymer in which the slightly water-soluble active substance is presentin amorphous form in the polymer matrix were found.

Furthermore, a process for the production of preparations of slightlywater-soluble active substances was found, the active substances beingpresent in amorphous form embedded in a polymer matrix based onpolyether copolymers of from 30 to 80% by weight of N-vinyllactam, from10 to 50% by weight of vinyl acetate and from 10 to 50% by weight of apolyether, wherein, in addition to the polyether copolymer, at least oneslightly water-soluble polymer is incorporated into the polymer matrix,and the polymers are thoroughly mixed with the slightly water-solubleactive substances.

The polyether copolymers present in the polymer matrix are obtained byfree radical polymerization of a mixture of

-   -   i) from 30 to 80% by weight of N-vinyllactam,    -   ii) from 10 to 50% by weight of vinyl acetate and    -   iii) from 10 to 50% by weight of a polyether,        with the proviso that the sum of i), ii) and iii) is equal to        100% by weight.

According to one process variant, the polyether copolymers arethoroughly mixed with slightly water-soluble polymers and the slightlywater-soluble active substances and the mixture is heated above theglass transition temperature of the copolymers.

According to a further process variant, the mixture of polymers andactive substances is prepared in organic solution and then dried.

The polyether copolymers are freely soluble in water, which means that,at 20° C., 1 part of copolymer dissolves in from 1 to 10 parts of water.

According to one embodiment of the invention, preferred polyethercopolymers, obtained from:

-   -   i) 30 to 70% by weight of N-vinyllactam    -   ii) 15 to 35% by weight of vinyl acetate, and    -   iii) 10 to 35% by weight of a polyether,        are used.

Particularly preferably used polyether copolymers are obtainable from:

-   -   i) 40 to 60% by weight of N-vinyllactam    -   ii) 15 to 35% by weight of vinyl acetate, and    -   iii) 10 to 30% by weight of a polyether.

Very particularly preferably used polyether copolymers are obtainablefrom

-   -   i) 50 to 60% by weight of N-vinyllactam    -   ii) 25 to 35% by weight of vinyl acetate, and    -   iii) 10 to 20% by weight of a polyether.

The proviso that the sum of the components i), ii), and iii) is equal to100% by weight also applies to the preferred and particularly preferredcompositions.

Suitable N-vinyllactam is N-vinylcaprolactam or N-vinylpyrrolidone or amixture thereof. N-Vinylcaprolactam is preferably used.

Polyethers serve as a grafting base. Preferred polyethers arepolyalkylene glycols. The polyalkylene glycols may have molecularweights of from 1000 to 100 000 D [Dalton], preferably from 1500 to 35000 D, particularly preferably from 1500 to 10 000 D. The molecularweights are determined starting from the OH number measured according toDIN 53240.

Particularly preferred polyalkylene glycols are polyethylene glycols.Furthermore, polypropylene glycols, polytetrahydrofurans or polybutyleneglycols, which are obtained from 2-ethyloxirane or 2,3-dimethyloxirane,are also suitable.

Other suitable polyethers are random or block copolymers of polyalkyleneglycols obtained from ethylene oxide, propylene oxide and butyleneoxides, such as, for example, polyethylene glycol-polypropylene glycolblock copolymers. The block copolymers may be of the AB type or of theABA type.

The preferred polyalkylene glycols also include those which arealkylated at one terminal OH group or at both terminal OH groups.Suitable alkyl radicals are branched or straight-chain C₁- to C₂₂-alkylradicals, preferably C₁-C₁₈-alkyl radicals, for example methyl, ethyl,n-butyl, isobutyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl, tridecylor octadecyl radicals.

General processes for the preparation of the polyether copolymersaccording to the invention are known per se. The preparation is effectedby free radical polymerization, preferably in solution, in nonaqueous,organic solvents or in mixed nonaqueous/aqueous solvents. Suitablepreparation processes are described, for example, in WO 2007/051743 andWO 2009/013202, the disclosure of which regarding the preparationprocess is hereby incorporated by reference.

For the targeted control of the release, the copolymers having thesolubilizing effect are used in combination with slightly water-solublepolymers which are suitable for influencing the release of thebiologically active substance. The extent to which the release isinfluenced depends here as a rule on the concentration of the slightlywater-soluble polymer.

The ratio of the polyether copolymer to the slightly water-solublepolymer may be from 99:1 to 10:90. Preferably, it is from 90:10 to 30:70and particularly preferably from 80:20 to 40:60.

Regarding the solubility of the polymers, the term “slightlywater-soluble” is to be understood as follows: according to theinvention, the term “slightly water-soluble” comprises slightly solubleand also practically insoluble substances and means that, for a solutionof the polymer in water at 20° C., from at least 100 to 1000 g of waterare required per g of polymer. In the case of practically insolublesubstances, at least 10 000 g of water are required per g of substance.

In the following description of the slightly water-soluble polymers, theterm “slightly water-soluble” is abbreviated to “slightly soluble”.

Slightly Water-Soluble Polymers

In the context of the invention, slightly water-soluble polymers areeither neutral slightly soluble polymers (sustained release polymers),anionic slightly soluble polymers (gastric resistant polymers) or basicslightly soluble polymers.

Neutral Slightly Soluble Polymers

Slightly soluble polymers are understood as meaning those polymers whichare slightly water-soluble or only swellable in water over the total pHrange from 1 to 14. As a rule, the pharmaceutical composition comprisesonly one water-insoluble polymer. However, two or more water-insolublepolymers may also be present alongside one another or as a mixture.

Examples of Suitable Slightly Soluble Polymers are:

Neutral or substantially neutral methacrylate copolymers. These maycomprise in particular at least 95, in particular at least 98,preferably at least 99, especially at least 99, particularly preferably100, % by weight of (meth)acrylate monomers subjected to free radicalpolymerization and having neutral radicals, in particular C1- toC4-alkyl radicals.

Suitable (meth)acrylate monomers having neutral radicals are, forexample, methyl methacrylate, ethyl methacrylate, butyl methacrylate,methyl acrylate, ethyl acrylate, butyl acrylate. Methyl methacrylate,ethyl acrylate and methyl acrylate are preferred. Methacrylate monomershaving anionic radicals, e.g. acrylic acid and/or methacrylic acid, maybe present in small proportions of less than 5, preferably not more than2, particularly preferably not more than 1 or from 0.05 to 1% by weight.

For example, neutral or virtually neutral (meth)acrylate copolymers offrom 20 to 40% by weight of ethyl acrylate, from 60 to 80% by weight ofmethyl methacrylate and from 0 to less than 5, preferably from 0 to 2 orfrom 0.05 to 1, % by weight (Eudragit® NE type) are suitable. EudragitNE is a copolymer of 30% by weight of ethyl acrylate and 70% by weightof methyl methacrylate.

Further suitable slightly soluble (meth)acrylate copolymers are, forexample, polymers which are soluble or swellable independently of pH andwhich are suitable for drug coatings.

The slightly soluble polymer may be a polymer of from 98 to 85% byweight of C1- to C4-alkyl esters of acrylic or of methacrylic acid andfrom 2 to 15% by weight of (meth)acrylate monomers having a quaternaryammonium group or a mixture of a plurality of polymers of this class ofsubstance.

The slightly soluble polymer may also be a polymer of from 97 to morethan 93% by weight of C1- to C4-alkyl esters of acrylic or ofmethacrylic acid and from 3 to less than 7% by weight of (meth)acrylatemonomers having a quaternary ammonium group (Eudragit® RS type).

Preferred C1- to C4-alkyl esters of acrylic or of methacrylic acid aremethyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate andmethyl methacrylate.

2-Trimethylammoniumethyl methacrylate chloride is particularly preferredas a (meth)acrylate monomer having quaternary amino groups.

A suitable copolymer by way of example comprises 65% by weight of methylmethacrylate, 30% by weight of ethyl acrylate and 5% by weight of2-trimethylammoniumethyl methacrylate chloride (Eudragit RS).

The slightly soluble polymer may be a polymer of from 93 to 88% byweight of C1- to C4-alkyl esters of acrylic or of methacrylic acid andfrom 7 to 12% by weight of (meth)acrylate monomers having a quaternaryammonium group (Eudragit RL type). A specifically suitable copolymercomprises, for example, 60% by weight of methyl methacrylate, 30% byweight of ethyl acrylate and 10% by weight of 2-trimethyl-ammoniumethylmethacrylate chloride (Eudragit® RL).

The water-insoluble polymer may be a mixture of polymers of the EudragitRS type and of the Eudragit RL type in the ratio of from 20:1 to 1:20.

Mixtures of Eudragit RS and Eudragit RL, for example in the ratio offrom 20:1 to 1:20 parts by weight, are also particularly suitable.

The pharmaceutical composition may also comprise a polyvinyl acetate asthe slightly soluble polymer. Suitable polyvinyl acetates are, forexample, the homopolymers of vinyl acetate. Furthermore, slightlysoluble polyvinyl acetate copolymers are suitable, for examplewater-insoluble copolymers of vinyl acetate and N-vinylpyrrolidone.

Commercially available suitable polyvinyl acetates are, for example,Kollicoat® SR 30D or Kollidon® SR.

Other suitable slightly soluble polymers are alkylcelluloses, such as,for example, ethylcellulose.

Anionic Slightly Soluble Polymers

Furthermore, anionic slightly soluble polymers may also be used. Anionicpolymers are understood as meaning preferably polymers having at least5%, particularly preferably from 5 to 75%, of monomer radicals withanionic groups. Anionic (meth)acrylate copolymers are preferred.Suitable commercially available (meth)acrylate copolymers having anionicgroups are, for example, the Eudragit® types L, L100-55, S and FS.Suitable anionic (meth)acrylate copolymers are, for example, polymers offrom 25 to 95% by weight of C1- to C4-alkyl esters of acrylic or ofmethacrylic acid and from 5 to 75% by weight of (meth)acrylate monomershaving an anionic group. Depending on the content of anionic groups andthe character of the further monomers at a pH above pH 5.0, appropriatepolymers are water-soluble and hence also soluble in intestinal fluid.As a rule, said proportions sum to 100% by weight.

A (meth)acrylate monomer having an anionic group may be, for example,acrylic acid, but preferably methacrylic acid.

Furthermore, anionic (meth)acrylate copolymers of from 40 to 60% byweight of methacrylic acid and from 60 to 40% by weight of methylmethacrylate or from 60 to 40% by weight of ethyl acrylate are suitable(Eudragit L or Eudragit L100-55 types). Eudragit L is a copolymer of 50%by weight of methyl methacrylate and 50% by weight of methacrylic acid.

Eudragit L100-55 is a copolymer of 50% by weight of ethyl acrylate and50% by weight of methacrylic acid. Eudragit L 30D-55 is a dispersioncomprising 30% by weight of Eudragit L100-55.

Also suitable are anionic (meth)acrylate copolymers of from 20 to 40% byweight of methacrylic acid and from 80 to 60% by weight of methylmethacrylate (Eudragit® S type).

For example, anionic (meth)acrylate copolymers consisting of from 10 to30% by weight of methyl methacrylate, from 50 to 70% by weight of methylacrylate and from 5 to 15% by weight of methacrylic acid (Eudragit® FStype) are furthermore suitable. Eudragit FS is a copolymer of 25% byweight of methyl methacrylate, 65% by weight of methyl acrylate and 10%by weight of methacrylic acid. Eudragit FS 30 D is a dispersioncomprising 30% by weight of Eudragit® FS.

The copolymers preferably comprise substantially to exclusively themonomers methacrylic acid, methyl acrylate and ethyl acrylate in theabovementioned proportions. However, small amounts in the range from 0to 10, e.g. from 1 to 5, % by weight of further vinylicallycopolymerizable monomers, such as, for example, methyl methacrylate,butyl methacrylate, butyl acrylate or hydroxyethyl methacrylate, mayadditionally be present without this leading to impairment of theessential properties.

The copolymers can be prepared by conventional continuous or batch freeradical mass, solution, bead or emulsion polymerization processes in thepresence of free radical initiators and, if appropriate, chain-transferagents for adjusting the molecular weight. The average molecular weightMw (weight average, determined, for example, by measuring the solutionviscosity) may be, for example, in the range from 80 000 to 1 000 000(g/mol). Emulsion polymerization in the aqueous phase in the presence ofwater-dissolved initiators and (preferably anionic) emulsifiers ispreferred. In the case of mass polymerization, the copolymer may beprocessed in solid form by crushing, extrusion, granulating or hot facecutting.

Also suitable as anionic polymer is hydroxypropyl methylcelluloseacetate succinate, a gastric resistant polymer which is soluble underbasic conditions.

Basic Slightly Soluble Polymers

It is also possible to use basic polymers, such as basic meth(acrylates)or chitosan. An example of a corresponding commercially availablepolymer is Eudragit® E or EPO, which is a copolymer of methylmethacrylate, butyl methacrylate and dimethylaminoethyl methacrylate.

The solid preparations can be prepared by methods known per se.

According to one embodiment, all ingredients of the preparations areinitially brought into solution together in a suitable solvent and thesolvent is then removed. Solvents which may be used are all solventscustomary in pharmaceutical technology, for example ethanol,isopropanol, n-butanol, isobutanol, ethyl acetate, acetone ordimethylformamide. The removal of the solvents can be effected via allpossible types of drying processes, for example via spray drying,fluidized-bed drying, drum drying, drying with the use of supercriticalgases, freeze-drying, evaporation.

According to a preferred procedure, the solid preparations are preparedby extrusion.

The polymers can be fed to the extruder both in pulverulent form and inthe form of solutions or dispersions.

The dispersions or solutions of the polymers can be converted into themolten state by removal of the dispersing medium or solvent in anextruder and into a solid form by cooling of the melt.

The melt thus obtained can then be cooled and granulated. For thispurpose, so-called hot face cutting or cooling under air or inert gas,for example on a Teflon belt or chain belt, and subsequent granulationof the cooled melt strand are effected. However, cooling can also beeffected in a solvent in which the polymers are not significantlysoluble.

The following methods A-E are in principle used:

A Physical powder mixture comprising polymers and active substance andfeeding of this polymer mixture into the extruder B Feeding of theactive substance via a separate bypass into nonmolten polymer mixture CFeeding of the active substance via a side metering means into moltenpolymers D Polymer solution with active substance dissolved or dispersedtherein, in partly devolatilized polymer melt or nonmolten polymermixture; E Processes according to A-D, solvent additionally beingintroduced into the extruder and evaporated again

In principle, the customary extruder types known to a person skilled inthe art are suitable for the process according to the invention. Theseusually comprise a housing, a drive unit with transmission and a processunit which consists of the extruder shaft or extruder shafts equippedwith the screw elements, a modular design being assumed in this case.

The extruder consists of a plurality of sections, which in each case areto be coordinated with certain process units. Each of these sectionsconsists of one or more barrels (barrel blocks) as a smallestindependent unit and the associated screw sections with the screwelements corresponding to the object of the process.

The individual barrels should be heatable. Furthermore, the barrels canalso be designed for cooling, for example for cooling with water. Theindividual barrel blocks are preferably heatable and coolableindependently of one another, so that different temperature zones can beestablished also along the extrusion direction.

The extruder is advantageously in the form of a twin-screw extruderhaving corotating screws. The screw configuration may provide differentdegrees of shearing depending on the product. Kneading elements must beused in particular in the melting zone. It is also possible to usereverse kneading elements.

Suitable twin-screw extruders may have a screw diameter of from 16 to 70mm and a length of from 25 to 40 D.

The total extruder is composed of barrel blocks which are individuallythermostatable. The first two barrels can be thermostated for thepurpose of better material intake. From the third barrel onward, it ispreferable to establish a constant temperature which should be chosen soas to be material-specific and is dependent in particular on the meltingpoint of the active substance used and on the glass transitiontemperature of the polymer. The resulting product temperature is,however, usually dependent on the degree of shearing of the screwelement used and may in some cases be 20-30° C. higher than the barreltemperature set.

A devolatilization zone which is advantageously operated at ambientpressure can be present downstream of the melting zone.

The round dies used may have a diameter of from 0.5 to 5 mm. Other dieshapes, such as slot dies, can likewise be used, especially when agreater material throughput is desired.

The two corotating screws are designed so that, downstream of a feedzone consisting of conveying elements, kneading blocks having adownstream flow restrictor are already used in the third heating zone.After a short decompression zone comprising conveying elements, the nowmolten material is thoroughly mixed again in a kneading zone. This isfollowed by a conveying element zone with downstream kneading elements.A conveying element zone with downstream kneading zone follows. Finally,the discharge of the material is ensured by a conveying element zone.

The resulting extrudates can be processed by means of a granulator togive pellets, and these in turn can be further comminuted (milled) togive a powder. The pellets or powder can be introduced into capsules orpressed to give tablets with the use of customary tableting assistants.In this case, it is also possible to use further excipients whichcontrol the release.

It is furthermore possible to use water, organic solvents, buffersubstances or plasticizers during the extrusion. In particular, water orvolatile alcohols are suitable for this purpose. This process permitsreactions at relatively low temperature. The amounts of solvent orplasticizer are usually from 0 to 30% of the extrudable materials. Thewater or solvent can be removed through a devolatilization point in theextruder at atmospheric pressure or by application of reduced pressure.Alternatively, these components evaporate when the extrudate leaves theextruder and the pressure decreases to atmospheric pressure. In the caseof sparingly volatile components, the extrudate can be subsequentlydried in an appropriate manner.

In a particular variant of the preparation process, the thermoplasticmaterial can be calendered, directly after the extrusion, to give atablet-like compact which constitutes the final administration form. Inthis variant, it may be expedient to add further constituents, such as,for example, polymers for adjusting the glass transition temperature andthe melt viscosity, disintegrants, solubilizers, plasticizers, dyes,flavorings, sweeteners, etc., before or during the extrusion. Inprinciple, these substance may also be used when the extrudate is firstcomminuted and then pressed to give tablets.

Water-soluble polymers having a high glass transition temperature, suchas, for example, polyvinylpyrrolidone having K values of 17-120,hydroxyalkylcelluloses or hydroxyalkyl-starches, can be used foradjusting the glass transition temperature of the formulation. Anexcessively high glass transition temperature of the formulation can bereduced by addition of plasticizers. All plasticizers which are alsoused for pharmaceutical coatings, such as, for example, triethylcitrate, tributyl citrate, acetyl tributyl citrate, triacetin, propyleneglycol, polyethylene glycol 400, dibutyl sebacate, glycerylmonostearate, lauric acid, cetyl stearyl alcohol, are in principlesuitable for this purpose.

Furthermore, surfactants which reduce the melt viscosity and hence theextrusion temperature can additionally be incorporated into thepreparations. These substances can also positively influence thepossible crystallization and bring about better wetting of theformulation and faster dissolution. Suitable substances are ionic andnonionic surfactants, such as, for example, Solutol® HS 15 (Macrogol 15Hydroxystearate), Tween® 80, polyoxyethylated fatty acid derivatives,such as Cremophor® RH40 (Polyoxyl 40 Hydrogenated Castor Oil, USP),Cremophor EL (Polyoxyl 35 Castor Oil, USP), poloxamers, docusate sodiumor sodium laurylsulfate.

The still plastic mixture is preferably extruded through a die, cooledand comminuted. In principle, all customary techniques known for thispurpose, such as hot face cutting or cold face cutting, are suitable forthe comminution.

The extrudate is face-cut, for example, by means of rotating blades orby means of an air jet and then cooled with air or under inert gas.

It is also possible to place the extrudate as a melt strand on a cooledbelt (stainless steel, Teflon, chain belt) and to granulate it aftersolidification.

The extrudate can then optionally be milled. The preparations areobtained as free-flowing and flowable water-soluble powders. Particlesizes of from 20 to 250 μm are preferably established.

Furthermore, it is also possible to process the plastic mixturecomprising the polymer and active substance by injection molding.

Surprisingly, the formulations according to the invention haveconsiderably improved stability, i.e. the active substance remains inthe molecularly disperse or colloidally disperse amorphous state in theformulation and does not crystallize. As a result, the releaseproperties too do not change over time. If the particle size of theextrudates is above 300 μm, the effect of the slightly water-solublepolymer on the release is evident. In these cases, this means that therelease is sustained or gastric resistant, depending on the addition.However, if the extrudate is comminuted so that the particle sizes arebelow 100 μm, a fast release is surprisingly achieved in the use ofgastric resistant or sustained-release polymers.

The preparations according to the invention have a higherbioavailability of the active substance.

The preparations obtained by the process according to the invention canbe used in principle in all areas where only slightly water-soluble orinsoluble substances are to be used in aqueous preparations or todisplay their effect in an aqueous medium.

In the context of the present invention, slightly water-solublesubstances are preferably to be understood as meaning biologicallyactive substances, such as pharmaceutical active substances for humansand animals, cosmetic or agrochemical active substances or foodsupplements or dietary active substances.

Furthermore, dyes, such as inorganic or organic pigments, are alsosuitable as slightly soluble substances to be solubilized.

The extrusion temperatures are usually in the range from 50 to 260° C.,preferably in the range of 70-200° C. The lower temperature limitdepends on the composition of the mixtures to be extruded and on theslightly soluble substances to be processed in each case. At least partof the mixture must be plasticizable at the chosen temperature. Theupper temperature limit is defined by the decomposition of the activesubstance or of the polymers.

The pharmaceutical active substances used are substances which areinsoluble or sparingly soluble in water, according to the definition inDAB 9.

According to DAB 9 (German Pharmacopeia), the solubility of substancesis classified as follows: sparingly soluble (soluble in from 30 to 100parts of solvent); slightly soluble (soluble in from 100 to 1000 partsof solvent); practically insoluble (soluble in more than 10 000 parts ofsolvent), based in each case on one part of substance to be dissolved at20° C.

The active substances may originate from any indication area.

Benzodiazepines, antihypertensives, vitamins, cytostatics—in particulartaxol, anesthetics, neuroleptics, antidepressants, antiviral agents,such as, for example, anti-HIV agents, antibiotics, antimycotics,antidementives, fungicides, chemotherapeutics, urologicals, plateletaggregation inhibitors, sulfonamides, spasmolytics, hormones,immunoglobulins, sera, thyroid therapeutics, psychopharmaceuticals,antiparkinson agents and other antihyperkinetics, ophthalmologicals,neuropathy preparations, calcium metabolism regulators, musclerelaxants, lipid-lowering agents, liver therapeutics, coronary agents,cardiac agents, immunotherapeutics, regulatory peptides and theirinhibitors, hypnotics, sedatives, gynecologicals, antigout agents,fibrinolytics, enzyme preparations and transport proteins, enzymeinhibitors, emetics, perfusion promoters, diuretics, diagnostics,corticoids, cholinergics, biliary therapeutics, antiasthmatics,bronchospasmolytics, beta-receptor blockers, calcium antagonists, ACEinhibitors, arteriosclerosis agents, anti-inflammatory agents,anticoagulants, antihypotensives, antihypoglycemics, antihypertonics,antifibrinolytics, antiepileptics, antiemetics, antidotes,antidiabetics, antiarrhythmics, antianemics, antiallergics,anthelmintics, analgesics, analeptics, aldosterone antagonists,weight-reducing agents may be mentioned here as examples.

Among the abovementioned pharmaceutical preparations, those which areorally administerable formulations are particularly preferred.

The content of the mixture of polyether copolymer and slightly solublepolymer in the pharmaceutical preparation is, depending on the activesubstance, in the range from 1 to 99% by weight, preferably from 5 to80% by weight, particularly preferably from 10 to 70% by weight.

For the preparation of the pharmaceutical administration forms, such as,for example, tablets, customary pharmaceutical excipients may be addedto the extrudates.

These are substances from the class consisting of fillers, plasticizers,solubilizers, binders, silicates and disintegrants and adsorbents,lubricants, flow improvers, dyes, stabilizers, such as antioxidants,wetting agents, preservatives, mold release agents, aromas orsweeteners, preferably fillers, plasticizers and solubilizers.

Fillers which may be added are, for example, inorganic fillers, such asoxides of magnesium, aluminum, silicon, titanium carbonate or calciumcarbonate, calcium phosphates or magnesium phosphates, or organicfillers, such as lactose, sucrose, sorbitol, mannitol.

Suitable plasticizers are, for example, triacetin, triethyl citrate,glyceryl monostearate, low molecular weight polyethylene glycols orpoloxamers.

Surface-active substances having an HLB value (hydrophilic-lipophilicbalance) greater than 11, for example hydrogenated castor oilethoxylated with 40 ethylene oxide units (Cremophor® RH 40), castor oilethoxylated with 35 ethylene oxide units (Cremophor EL), polysorbate 80,poloxamers, docusate sodium or sodium laurylsulfate, are suitable asadditional solubilizers.

Stearates of aluminum, calcium, magnesium and tin, and magnesiumsilicate, silicones and the like can be used as lubricants.

For example, talc or colloidal silica can be used as flow improvers.

For example, microcrystalline cellulose is suitable as a binder.

For additional adjustment of delayed release, further slightlywater-soluble polymers may also be added to the tableting mixtures.

Disintegrants may be crosslinked polyvinylpyrrolidone or crosslinkedsodium carboxymethyl-starch. Stabilizers may be ascorbic acid ortocopherol.

Dyes are, for example, iron oxides, titanium dioxide, triphenylmethanedyes, azo dyes, quinoline dyes, indigotin dyes, carotinoids, forcoloring the administration forms, opacifying agents, such as titaniumdioxide or talc, for increasing the light transmittance and decreasingthe use of dyes.

In addition to use in cosmetics and pharmacy, the preparations producedaccording to the invention are also suitable for use in the food sector,for example for the incorporation of slightly water-soluble orwater-insoluble nutrients, assistants or additives, such as, forexample, fat-soluble vitamins or carotinoids. Beverages colored withcarotinoids may be mentioned as examples.

The use of the preparations obtained according to the invention inagrochemistry may comprise, inter alia, formulations which comprisepesticides, herbicides, fungicides or insecticides, especially thosepreparations of crop protection agents to be used as formulations forspraying or watering.

So-called solid solutions of slightly soluble substances can be obtainedwith the aid of the process according to the invention. According to theinvention, systems in which no crystalline fractions of the slightlysoluble substance are observable are designated as solid solutions.

On visual assessment of the stable solid solutions, no amorphousconstituents are evident. The visual assessment can be effected using anoptical microscope, either with or without polarization filters under 40times magnification.

Furthermore, the preparations can also be investigated with regard tocrystallinity or amorphous properties with the aid of XRD (X-raydiffraction) and DSC (differential scanning calorimetry).

The preparations obtained by the process according to the invention arepresent, as stated, in amorphous form, which means that the crystallinefractions of the biologically active substance are less than 5% byweight. Preferably, the amorphous state is checked by means of DSC orXRD. Such an amorphous state may also be designated as X-ray amorphousstate.

The process according to the invention permits the production of stablepreparations having a high active substance loading and good stabilitywith regard to the amorphous state of the slightly soluble substance.

The process according to the invention permits the production of stablepreparations having a high active substance loading.

EXAMPLES Preparation of Polymer 1

In a stirred apparatus, the initially taken mixture was heated to 77° C.under an N₂ atmosphere without the portion of feed 2. When the internaltemperature of 77° C. was reached, the portion of feed 2 was added andprepolymerization was effected for 15 min. Thereafter, feed 1 wasmetered in in 5 h and feed 2 in 2 h. After all feeds had been meteredin, the reaction mixture was subsequently polymerized for a further 3 h.After subsequent polymerization, the solution was adjusted to a solidscontent of 50% by weight.

Initially taken mixture: 25 g of ethyl acetate

-   -   104.0 g of PEG 6000,    -   1.0 g of feed 2

Feed 1: 240 g of vinyl acetate

Feed 2: 456 g of vinylcaprolactam

-   -   240 g of ethyl acetate

Feed 3: 10.44 g of tert-butyl perpivalate (75% strength by weight inaliphatics mixture)

-   -   67.90 g of ethyl acetate.

Thereafter, the solvent was removed by a spray process and a pulverulentproduct was obtained. The K value was 16, measured as a 1% strength byweight solution in ethanol.

The twin-screw extruder which was used for the preparation of theformulations described in the following examples had a screw diameter of16 mm and a length of 40D. The entire extruder was composed of 8individual thermostatable barrel blocks. The first two barrels werethermostated at 20° C. and at 70° C., respectively, for the purpose ofbetter material intake. From the third barrel onward, a constanttemperature was established.

The solid solutions prepared were investigated by means of XRD (X-raydiffractometry) and DSC (differential scanning calorimetry) with regardto crystallinity and amorphous properties, using the followingapparatuses and conditions:

XRD

Measuring apparatus: D 8 Advance diffractometer with 9-tube samplechanger (from Bruker/AXS)

Measurement method: θ-θ geometry in reflection

2 theta angle range: 2-80°

Step width: 0.02°

Measuring time per angle step: 4.8 s

Divergence slit: Gbbel mirror with 0.4 mm inserted aperture

Antiscattering slit: Soller slit

Detector: Sol-X detector

Temperature: room temperature

Generator setting: 40 kV/50 mA

DSC

DSC Q 2000 from TA-Instruments

Parameters:

Weight taken about 8.5 mg

Heating rate: 20K/min

The active substance release was effected according to the USP apparatus(paddle method 2), 37° C., 50 rpm (BTWS 600, Pharmatest). The extrudateswere comminuted to a length of 3 mm by means of a granulator and wereintroduced into hard gelatin capsules. The detection of the activesubstance released was effected by UV spectroscopy (Lamda-2, PerkinElmer).

Example 1

1200 g of polymer 1, 400 g of Eudragit E PO and 400 g of Celecoxib(melting point 162° C.) were weighed into a Turbula mixing container andmixed for 10 minutes in the Turbula mixer T10B.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel onward: 140° C.    -   Screw speed 200 rpm    -   Throughput: 500 g/h    -   Die diameter 3 mm

The solid solutions were investigated by XRD and by DSC and were foundto be amorphous. After 1 h in 0.1 normal HCl, 95% of active substancehad been released. After storage for 6 months at 30° C./70% relativehumidity, the preparations were still amorphous.

Example 2

800 g of polymer 1, 800 g of Eudragit E PO and 400 g of Naproxen(melting point 157° C.) were weighed into a Turbula mixing container andmixed for 10 minutes in the Turbula mixer T10B.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel onward: 120° C.    -   Screw speed 200 rpm    -   Throughput: 600 g/h    -   Die diameter 3 mm

The solid solutions were investigated by XRD and by DSC and found to beamorphous. After 1 h in 0.1 normal HCl, 89% of active substance had beenreleased.

Example 3

1200 g of polymer 1, 400 g of Eudragit E PO, 40 g of sodiumlaurylsulfate and 400 g of itraconazole (melting point 166° C.) wereweighed into a Turbula mixing container and mixed for 10 minutes in theTurbula mixer T10B.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel: 140° C.    -   Screw speed 200 rpm    -   Throughput: 800 g/h    -   Dye diameter 3 mm

The solid solutions were investigated by XRD and by DSC and found to beamorphous. After 1 h in 0.1 normal HCl, 99% of active substance had beenreleased.

After storage for 6 months at 30° C./70% relative humidity, thepreparations were still amorphous.

Example 4

600 g of polymer 1, 1000 g of Kollidon SR and 400 g of fenofibrate(melting point 81° C.) were weighed into a Turbula mixing container andmixed for 10 minutes in the Turbula mixer T10B.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel: 110° C.    -   Screw speed 200 rpm    -   Throughput: 1000 g/h    -   Dye diameter 3 mm

The solid solutions were investigated by XRD and by DSC and found to beamorphous. The release of the active substance in 0.1 normal HCl after 2h was less than 20%. After rebuffering to pH 6.8, this was for a further10 h, after which altogether 80% of active substance was released.

After storage for 6 months at 30° C./70% relative humidity, thepreparations were still amorphous.

Example 5

600 g of polymer 1, 1000 g of Eudragit S 100 and 400 g of cinnarizine(melting point 122° C.) were weighed into a Turbula mixing container andmixed for 10 minutes in the Turbula mixer T10B. Triethyl citrate was fedinto the extruder via a reciprocating piston pump.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel: 130° C.    -   Screw speed 100 rpm    -   Throughput: 800 g/h    -   Liquid metering: 80 g/h    -   Dye diameter 3 mm

The solid solutions were investigated by XRD and by DSC and found to beamorphous. The release of the active substance in 0.1 normal HCl after 2h was less than 10%; after rebuffering to pH 6.8, 100% were released.

After storage for 6 months at 30° C./70% relative humidity, thepreparations were still amorphous.

Example 6

400 g of polymer 1, 1200 g of Eudragit E PO and 400 g of carbamazepine(melting point 192° C.) were weighed into a Turbula mixing container andmixed for 10 minutes in the Turbula mixer T10B.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel: 160° C.    -   Screw speed 200 rpm    -   Throughput: 600 g/h    -   Dye diameter 3 mm

The solid solutions were investigated by XRD and by DSC and found to beamorphous. After 1 h in 0.1 normal HCl, 95% of active substance had beenreleased.

After storage for 6 months at 30° C./70% relative humidity, thepreparations were still amorphous.

Example 7

600 g of polymer 1, 1000 g of Eudragit L 100-55 and 400 g of loperamide(melting point 223° C.) were weighed into a Turbula mixing container andmixed for 10 minutes in the Turbula mixer T10B.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel: 170° C.    -   Screw speed 200 rpm    -   Throughput: 1000 g/h    -   Dye diameter 3 mm

The solid solutions were investigated by XRD and by DSC and found to beamorphous. The release of the active substance in 0.1 normal HCl after 2h was less than 10%; after rebuffering to pH 6.8, 98% were released.

After storage for 6 months at 30° C./70% relative humidity, thepreparations were still amorphous.

Example 8

600 g of polymer 1, 500 g of Eudragit RS PO, 500 g of Eudragit RL PO and400 g of clotrimazole (melting point 148° C.) were weighed into aTurbula mixing container and mixed for 10 minutes in the Turbula mixerT10B.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel: 150° C.    -   Screw speed 100 rpm    -   Throughput: 700 g/h    -   Dye diameter 3 mm

The solid solutions were investigated by XRD and by DSC and found to beamorphous. The release of the active substance in phosphate buffer pH6.8 was 20% after 2 h; after 10 h, 84% of the active substanceoriginally used had been released. After storage for 6 months at 30° C.,the preparations were still amorphous.

Example 9

600 g of polymer 1, 1000 g of HPMCAS (hydroxypropyl methylcelluloseacetate succinate) and 400 g of cinnarizine (melting point 122° C.) wereweighed into a Turbula mixing container and mixed for 10 minutes in theTurbula mixer T10B.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel: 140° C.    -   Screw speed 100 rpm    -   Throughput: 800 g/h    -   Dye diameter 3 mm

The solid solutions were investigated by XRD and by DSC and found to beamorphous. The release of the active substance in 0.1 normal HCl after 2h was less than 10%; after rebuffering to pH 6.8, 90% were released.

After storage for 6 months at 30° C./70% relative humidity, thepreparations were still amorphous.

Example 10

600 g of polymer 1, 500 g of Eudragit RS PO, 500 g of Eudragit RL PO and400 g of piroxicam (melting point 199° C.) were weighed into a Turbulamixing container and mixed for 10 minutes in the Turbula mixer T10B.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel: 170° C.    -   Screw speed 100 rpm    -   Throughput: 700 g/h    -   Dye diameter 3 mm

The solid solutions were investigated by XRD and by DSC and found to beamorphous. The release of the active substance in phosphate buffer pH6.8 was 20% after 2 h; after 10 h, 93% of the active substanceoriginally used had been released.

After storage for 6 months at 30° C./70% relative humidity, thepreparations were still amorphous.

Example 11

600 g of polymer 1, 1000 g of ethylcellulose and 400 g of felodipine(melting point 145° C.) were weighed into a Turbula mixing container andmixed for 10 minutes in the Turbula mixer T10B. Eudragit NE 40D was fedinto the extruder via a reciprocating piston pump.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel: 140° C.    -   Screw speed 100 rpm    -   Throughput: 800 g/h    -   Liquid metering: 60 g/h    -   Dye diameter 3 mm

The solid solutions were investigated by XRD and by DSC and found to beamorphous. The release of the active substance in phosphate buffer pH6.8 was 31% after 2 h; after 10 h, 79% of the active substanceoriginally used had been released.

After storage for 6 months at 30° C./70% relative humidity, thepreparations were still amorphous.

Example 12

600 g of polymer 1, 1000 g of Eudragit RS PO and 400 g of itraconazole(melting point 166° C.) were weighed into a Turbula mixing container andmixed for 10 minutes in the Turbula mixer T10B.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel: 150° C.    -   Screw speed 100 rpm    -   Throughput: 800 g/h    -   Dye diameter 3 mm

The solid solutions were investigated by XRD and by DSC and found to beamorphous. The release of the active substance in phosphate buffer pH6.8 was 27% after 2 h; after 10 h, 82% of the active substanceoriginally used had been released.

After storage for 6 months at 30° C./70% relative humidity, thepreparations were still amorphous.

Example 13

400 g of polymer 1, 1200 g of Eudragit RL PO and 400 g of carbamazepine(melting point 192° C.) were weighed into a Turbula mixing container andmixed for 10 minutes in the Turbula mixer T10B.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel: 160° C.    -   Screw speed 100 rpm    -   Throughput: 800 g/h    -   Dye diameter 3 mm

The solid solutions were investigated by XRD and by DSC and found to beamorphous. The release of the active substance in HCl after 2 h was lessthan 20%. After rebuffering to pH 6.8, 75% were released after 10 h.

After storage for 6 months at 30° C./70% relative humidity, thepreparations were still amorphous.

Example 14

1200 g of polymer 1, 400 g of Eudragit E PO, 20 g of docusate sodium and400 g of fenofibrate (melting point 81° C.) were weighed into a Turbulamixing container and mixed for 10 minutes in the Turbula mixer T1013.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel: 120° C.    -   Screw speed 100 rpm    -   Throughput: 800 g/h    -   Dye diameter 3 mm

The solid solutions were investigated by XRD and by DSC and found to beamorphous. The release of the active substance in HCl after 2 h was 83%.

After storage for 6 months at 30° C., the preparations were stillamorphous.

Example 15

600 g of polymer 1, 500 g of Kollidon SR, 500 g of ethylcellulose, 20 gof Cremophor RH40 and 400 g of clotrimazole (melting point 148° C.) wereweighed into a Turbula mixing container and mixed for 10 minutes in theTurbula mixer T10B.

Kollidon SR: physical mixture of 80% by weight of polyvinyl acetate, 19%by weight of polyvinylpyrrolidone k30, 0.8% by weight of sodiumlaurylsulfate, 0.2% by weight of silicon dioxide.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel: 160° C.    -   Screw speed 100 rpm    -   Throughput: 700 g/h    -   Dye diameter 3 mm

The solid solutions were investigated by XRD and by DSC and found to beamorphous. The release of the active substance in 0.1 normal HCl after 2h was less than 20%.

After rebuffering to pH 6.8, 87% were released after 10 h.

After storage for 6 months at 30° C./70% relative humidity, thepreparations were still amorphous.

Example 16

600 g of polymer 1, 1000 g of HPMCAS and 400 g of fenofibrate (meltingpoint 81° C.) were weighed into a Turbula mixing container and mixed for10 minutes in the Turbula mixer T10B.

The mixture was extruded under the following conditions:

-   -   Zone temperature of 1st barrel: 20° C.; 2nd barrel: 40° C.    -   Zone temperature from the 3rd barrel: 120° C.    -   Screw speed 100 rpm    -   Throughput: 800 g/h    -   Dye diameter 3 mm

The solid solutions were investigated by XRD and by DSC and found to beamorphous. The release of the active substance in 0.1 normal HCl after 2h was less than 10%; after rebuffering to pH 6.8, 100% were released.

Example 17

The extrudate from Example 7 was comminuted by means of an air jet millto a particle size of less than 25 μm. The release of the activesubstance in 0.1 normal HCl after 1 h was 82%.

Example 18

The extrudate from Example 15 was comminuted by means of an air jet millto a particle size of less than 20 μm. The release of the activesubstance in 0.1 normal HCl after 1 h was 79%.

1. A dosage form comprising preparations of slightly water-solubleactive substances in a polymer matrix of polyether copolymers, thepolyether copolymers being obtained by free radical polymerization of amixture of from 30 to 80% by weight of N-vinyllactam, from 10 to 50% byweight of vinyl acetate and from 10 to 50% by weight of a polyether, andof at least one slightly water-soluble polymer in which the slightlywater-soluble active substance is present in amorphous form in thepolymer matrix.
 2. The dosage form according to claim 1, wherein theslightly water-soluble polymers comprise those polymers whose solubilityin water is pH-dependent.
 3. The dosage form according to claim 1,wherein the slightly water-soluble polymers are based on acrylic acid ormethacrylic acid or esters thereof or mixtures of said monomers.
 4. Thedosage form according to claim 1, wherein the slightly water-solublepolymers comprise homo- and copolymers of vinyl acetate.
 5. The dosageform according to claim 1, wherein the slightly water-soluble polymerscomprise ethylcelluloses.
 6. The dosage form according to claim 1,wherein the ratio of the polyether copolymer to the slightlywater-soluble polymer is from 99:1 to 10:90.
 7. The dosage formaccording to claim 1, wherein the ratio of the polyether copolymer tothe slightly water-soluble polymer is from 90:10 to 30:70.
 8. The dosageform according to claim 1, wherein the ratio of the polyether copolymerto the slightly water-soluble polymer is from 80:20 to 40:60.
 9. Thedosage form according to claim 1, in which the polymer matrix furthercomprises a solubilizer.
 10. A process for the production ofpreparations for dosage forms of slightly water-soluble activesubstances according to claim 1, the active substances being present inamorphous form embedded in a polymer matrix based on polyethercopolymers of from 30 to 80% by weight of N-vinyllactam, from 10 to 50%by weight of vinyl acetate and from 10 to 50% by weight of a polyether,wherein, in addition to the polyether copolymer, at least one slightlywater-soluble polymer is incorporated into the polymer matrix, and thepolymers are thoroughly mixed with the slightly water-soluble activesubstances.
 11. The process according to claim 10, wherein the mixtureof polymers and active substances is heated above the glass transitiontemperature of the polyether copolymers.
 12. The process according toclaim 10, wherein the mixing of polymers and active substances iseffected in an extruder.
 13. The process according to claim 10, whereinthe mixing of polymers and active substances is effected in organicsolution, and the organic solvents are then removed.
 14. The processaccording to claim 13, wherein the organic solvents are removed by spraydrying.
 15. The dosage form according to claim 2 wherein the polymerswhose solubility in water is pH-dependent are based on acrylic acid ormethacrylic acid or esters thereof or mixtures of said monomers.
 16. Thedosage form according to claim 15 wherein the ratio of the polyethercopolymer to the slightly water-soluble polymer is from 99:1 to 10:90.17. The dosage form according to claim 15, in which the polymer matrixfurther comprises a solubilizer.
 18. The dosage form according to claim4 wherein the ratio of the polyether copolymer to the slightlywater-soluble polymer is from 99:1 to 10:90.
 19. The dosage formaccording to claim 15 wherein the ratio of the polyether copolymer tothe slightly water-soluble polymer is from 90:10 to 30:70.
 20. Thedosage form according to claim 15, wherein the ratio of the polyethercopolymer to the slightly water-soluble polymer is from 80:20 to 40:60.